The American Cancer Society estimated that, in 2006, over 60,000 Americans would develop cancer of the urinary bladder, and that over 13,000 Americans would die of it. Bladder cancer is the fourth most common cancer in American men, and the eighth most common in women. The U.S. National Cancer Institute (“NCI”) estimated that, of the 60,000 who were expected to develop the disease in 2006, 70 to 80% of the patients would be diagnosed with superficial bladder tumors, that is, tumors staged at stage Ta, Tis, or T1. Such early stage tumors can usually be successfully treated by transurethral resection of the bladder, with follow up by cystoscopy (that is, visualization of the interior surface of the bladder through a cystoscope introduced through the urethra) to detect whether tumors recur following removal of the first. The remaining patients present with more invasive tumors. Some 50% of these patients have muscle-invasive disease and have their bladders removed, which is known as radical cystectomy.
According to the NCI, invasive tumors that are confined to the bladder muscle on pathologic staging after radical cystectomy are associated with approximately a 75% 5-year progression-free survival rate. Patients with more deeply invasive tumors, which are also usually less well differentiated, and those with lymphovascular invasion experience 5-year survival rates of 30% to 50% following radical cystectomy. When the patient presents with locally extensive tumor that invades pelvic viscera or with metastases to lymph nodes or distant sites, 5-year survival is uncommon. Thus, determining the extent to which tumor cells have spread to lymph nodes is important in determining the patient's prognosis.
Lymph nodes which receive drainage from a cancerous organ are known as sentinel lymph nodes. As described by Roger Uren, Nature Biotech, 22:38-9 (2004), “[l]ymphatic drainage is mapped from a primary tumor site to the draining lymph node or nodes, and these are then removed for detailed histological examination. If the sentinel node is normal, all of the lymph nodes in the node field can be assumed to be normal.” Sentinel lymph node (for convenience, sometimes referred to herein as “sentinel node” or “SLN”) biopsies therefore can permit sparing other lymph nodes which may be present in the pelvic area, reducing trauma to the patient while maintaining or improving prognosis. As Uren further notes, however, such biopsies are very difficult to perform accurately in patients. Thus, methods of accurately identifying sentinel lymph nodes are of great interest.
Several methods have been explored for detecting sentinel nodes in patients with bladder cancer. The histopathological status of the identified SLNs was diagnostic for all other excised lymph nodes. Sentinel nodes often seem to be located outside the obturator lymphatic field, which is normally examined during preoperative staging of bladder cancer. (Sherif et al., J Urol., 165(3):812-815 (2001)). Liedberg et al., Aktuelle Urol, 34(2): 115-118 (2003) studied 28 patients scheduled for cystectomy using preoperative lymphoscintigraphy, perioperative dye detection (Patent Blue) and dynamic lymphoscintigraphy. The substances were injected adjacent to the tumor in the detrusor muscle. Sentinel nodes were detected in 21 of 26 of the investigated patients. Seven of 21 SLN were located outside the obturator fosse. Of the eight patients with lymph node metastasis, five displayed metastasis in lymph nodes outside the obturator fossa. There was one false negative SLN in a patient with multifocal tumor, while in the other seven patients with lymph node metastasis, these were detected in the SLN. The authors concluded that sentinel node detection is possible in most cases of bladder cancer scheduled for cystectomy. In their updated series, Liedberg et al. reported that, in 75 patients, 81% had SLNs detected. (Liedberg et al., J Urol., 175(1):84-88 (2006)). Of the 32 lymph node positive cases 26 (81%) had a positive (metastatic) SN. Thus, the false-negative rate was 6 of 32 cases (19%). Five false-negative cases had macrometastases and/or perivesical metastases. In 9 patients (14%), the SLN contained micrometastases (less than 2 mm), in 5 of whom the micrometastasis was the only metastatic deposit. Thus, this method had a relatively high rate of false-negatives.
A variety of medical techniques have been used for imaging biological tissues and organs. These include traditional x-rays, ultra-sound, magnetic resonance imaging (“MRI”), and computerized tomography (“CT”). Techniques such as MRI, micro-CT, micro-positron emission tomography (“PET”), and single photon emission computed tomography (“SPECT”) have been explored for imaging function and processes in small animals or in vivo, intra operatively. These technologies offer deep tissue penetration and high spatial resolution, but are costly and time consuming to implement.
Several new, nanoparticle systems for imaging sentinel lymph nodes are in development. One of these new systems uses so-called “dendrimers”, or spherical polymers, to carry agents such as the MRI contrast agent gadolinium to visualize nodes. In another, “nanocrystals,” or “quantum dots,” made of silicon or similar materials, can be “tuned” to fluoresce in the near infrared.
It would be desirable to have additional methods for imaging sentinel lymph nodes of bladder cancer patients undergoing radical cystectomy or other procedures for aggressive or advanced disease.